Utility of Sputum Induction and Novel Technologies to Improve TB Diagnosis in a High HIV Prevalence Primary Care Setting (SINET)

A Randomised Control Trial of Sputum Induction, and New and Emerging Technologies in a High HIV Prevalence Primary Care Setting

This study will investigate the benefit of using Sputum induction for TB diagnosis in a primary care clinic for adult TB suspects that are either unable to produce a sputum sample (sputum scarce) or on initial diagnostic work-up have 2 negative sputum smear samples (WHO standard for frontline TB diagnosis). The investigators hypothesize that acquiring an induced sputum sample for smear microscopy and liquid TB culture will decrease time-to-diagnosis and time-to-treatment initiation in smear negative/sputum scarce TB patients in a primary care clinic in a resource-limited high TB HIV prevalent setting.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Procedure: Sputum induction; Procedure: standard routine expectorated sputum

Detailed Description

Tuberculosis is on the increase in Africa. A key area of weakness in TB control efforts is the inability to make a rapid diagnosis. This is, in part, due to the inability to obtain representative biological samples and the non-availability of cheap, effective, rapid and field-friendly diagnostic tools. Indeed, in HIV positive patients, where the sensitivity of sputum smear is as low as 20%, culture results take several weeks and a significant proportion of patients do not expectorate sputum. Sputum induction for the diagnosis of TB has been evaluated in several studies, has been shown to have a good yield, feasibility and safety when performed correctly, and with diagnostic comparability to bronchoscopy. Few studies have evaluated the performance of induced sputum outside of the hospital environment and the tolerability, yield and performance outcome of sputum induction in a primary care facility has yet to be evaluated. The objective of this study is two-fold. We seek to evaluate, through a randomized controlled trial, the feasibility, performance outcomes and impact on time-to-diagnosis and -treatment of sputum induction, in a high HIV prevalence primary care setting, for the diagnosis of smear negative/ sputum scarce TB. We hypothesize that acquiring an induced sputum sample for smear microscopy and liquid TB culture will decrease time-to-diagnosis and time-to-treatment initiation in smear negative/sputum scarce TB patients in a primary care clinic in a resource-limited high TB HIV prevalent setting. We will also evaluate the potential incremental benefit of novel technologies to improve the rapidity and diagnostic yield using induced sputum samples (Xpert MTB/RIF assay, microscopic observation drug susceptibility testing (MODS) and the Genotype MTB DRplus line probe assay).

• Study Type: Interventional
• Enrollment (Actual): 517
• Phase: Not Applicable

Contacts and Locations

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7945
      • University of Cape Town

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 2x smear negative or sputum scarce TB suspects
2. Primary care patient (not referred by doctor)
3. Adult patients (>18 years)
4. Able to provide informed consent

Exclusion Criteria:

1. Not meeting inclusion criteria
2. <18 years
3. Unable to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sputum induction; Enrolled patients receive sputum induction (using ultrasonic nebulisation with hypertonic saline)	Procedure: Sputum induction; Ultrasonic nebulisation 3% hypertonic saline nebulised for duration of 20 mins
Active Comparator: No sputum induction; Enrolled patients randomised to this study arm will receive an observed expectorated sputum collection attempt. Research nurses train study patients on the method of producing sputum spontaneously.	Procedure: standard routine expectorated sputum; Patients in the control group are trained by the research staff to produce sputum but no device is utilized. Sputum is spontaneously expectorated where possible

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-treatment initiation	Time-specific proportion of patients initiated on TB treatment between study arms Time-points to be analysed include 3, 5, 7, 10, 14, 21, 48 days from enrollment.	Up to 48 days after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic yield of sputum culture	Difference in diagnostic yield of a single sputum TB culture between study arms. This will compare the single induced or expectorated sputum sample collected at study enrollment.	Up to 2 months after enrollment
Diagnostic yield and accuracy of sputum smear microscopy	Difference in diagnostic yield and accuracy of a single sputum TB smear between study arms. This will compare the single induced or expectorated sputum sample collected at study enrollment. Liquid TB culture will be used as the reference standard for assessment of diagnostic accuracy Fluorescence smear microscopy will be performed on auramine-O stained concentrated samples	Up to 2 months after enrollment
Feasibility of sputum induction in primary care clinics	Feasibility and robustness of performing sputum induction in primary care clinics (measures include - sputum induction failure rates, turn-around-time, user appraisals and evaluation)	2 years
Safety and tolerability of sputum induction performed in primary care clinics	Side-effects of sputum induction procedures Number of induced sputum procedures terminated because of patient side-effects and safety	2 years
Diagnostic yield and accuracy of additional diagnostics including Xpert MTB/RIF assay, MODS and Genotype MTBDRplus	Difference in diagnostic yield and accuracy of Xpert MTB/RIF, MODS liquid culture and the Genotype MTBDRplus on a single induced or expectorated sputum sample collected at enrollment. Liquid TB culture will be used as the reference standard for diagnostic accuracy measures.	2 years
Cost-analysis of sputum induction for primary care clinics	Based on diagnostic accuracy measures of different diagnostic tests between the induced sputum and standard care groups, cost-of-diagnosis will be calculated and compared	2 years

Collaborators and Investigators

• Sponsor: University of Cape Town
• Investigators: Principal Investigator: Jonathan G Peter, MBChB, University of Cape Town

Publications and helpful links

General Publications

• Peter JG, Theron G, Pooran A, Thomas J, Pascoe M, Dheda K. Comparison of two methods for acquisition of sputum samples for diagnosis of suspected tuberculosis in smear-negative or sputum-scarce people: a randomised controlled trial. Lancet Respir Med. 2013 Aug;1(6):471-8. doi: 10.1016/S2213-2600(13)70120-6. Epub 2013 Jul 19.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: July 7, 2011
• First Submitted That Met QC Criteria: March 1, 2012
• First Posted (Estimate): March 7, 2012

Study Record Updates

• Last Update Posted (Estimate): December 24, 2012
• Last Update Submitted That Met QC Criteria: December 21, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: primary care; Tuberculosis; diagnosis; sputum induction
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: SINET study